8/23/2017 Measles virus

HumVaccinImmunother.2015Jan11(1):2126. PMCID:PMC4514292
Publishedonline2014Aug5.doi:10.4161/hv.34298

Measlesvirus
Apathogen,vaccine,andavector
HusseinYNaim*,1
1
LifeSciencesandVaccinesConsultantBern,Switzerland
*
Correspondenceto:HusseinYNaim,Email:hussein.naim@bluewin.ch

Received2014Aug4Accepted2014Aug4.

Copyright2015LandesBioscience

ThisarticlehasbeencitedbyotherarticlesinPMC.

Abstract Goto:

Measleswasaninevitableinfectionduringthehumandevelopmentwithsubstantialdegreeof
morbidityandmortality.Theseverityofmeaslesvirus(MV)infectionwaslargelycontainedbythe
developmentofaliveattenuatedvaccinethatwasintroducedintothevaccinationprograms.However,
alleffortstoeradicatethediseasefailedandcontinuedtoannuallyresultinsignificantdeaths.The
developmentofmolecularbiologytechniquesallowedtherescueofMVfromcDNAthatenabled
importantinsightsintoavarietyofaspectsofthebiologyofthevirusanditspathogenesis.
Subsequentlythesetechnologiesfacilitatedthedevelopmentofnovelvaccinecandidatesthatinduce
immunityagainstmeaslesandotherpathogens.Basedonthepromisingprospective,theuseofMVas
arecombinantvaccineandatherapeuticvectorisaddressed.

Keywords:measles,pathogenesis,SSPE,vaccine,liveviralvaccine,viralvectors,recombinant
vaccines

Introduction Goto:

Measles,alsoknownasmorbilli,isaninfectionoftherespiratorysystem,immunesystemandskin
causedbymeaslesvirus(MV),aparamyxovirusofthegenusMorbillivirus.Measlesisan
exceptionallycontageousviralinfectionwithasubstantialdegreeofmorbidityandsignificant
mortality.1Beforeaneffectivevaccinebecameavailable,measleswasaninevitablestepinhuman
development.Infactthefirstscientificdescriptionofmeaslesanditsdistinctionfromsmallpoxand
chickenpoxiscreditedtothePersianphysicianRhazes(860932),TheBookofSmallpoxand
Measles.2Thesymptomsusuallydevelop714dafterexposuretothevirus.Theinitialsymptoms
usuallyincludeahighfever(often>40C),Koplikspots(spotsinthemouththatusuallyappear23d
priortotherashandlast35d),malaise,lossofappetite,redeyes,runnynose,andsometimescough.3
Aculminationofgeneralizedsystemicinfectionoccurswiththeappearanceoftypicalmaculopapular,
erythematousrashthatcoversmuchofthebodyafterwhichtherecoveryprogresses,providedthat
therearenootherinfectionsorcomplications.4

Pathogenesisofmeaslesvirus Goto:

SinceMVishighlycontagious,90%ofpeoplenotimmuneagainstthevirusbutsharinglivingspace
withaninfectedpersonwillcatchit.Thevirusspreadsbyrespirationeitherdirectlyorthrough
aerosol.5Thevirusentersthehostthroughtheupperrespiratorypassagesandinfectstherespiratory
epitheliumand/orthecirculatingimmunecellslocatedatthatsite.Thevirusinfectsthehostbybinding
specificallytoitsreceptors:SLAM(signalinglymphocyteactivationmolecule)thatisexpressedon

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immunecells,theCD46(membranecofactorprotein)thatisexpressedonepithelialcells,andathird
putativereceptorthatisshowntoallowMVinfectionwiththeabsenceoftheabovereceptors.68This
typeofreceptormediatedentryconfinedthetropismofMVtohumansalthoughnonhumanprimates
andsomerodentsarepermissivetoMV,nootheranimalreservoirsareknowntoexist.911Afteran
exposuretoMVanasymptomaticincubationperiodoccursnineto12days.Theperiodofinfectivityto
appearanceofsymptomshasnotbeendefinitivelyestablished,howevertheclassicaloracute
measlesdevelopsafteranincubationperiodofapproximately10days.Theinfectedchildtendsto
developamildrespiratoryillness,easilyconfusedwithcommoncold.Astheseverityofthesymptoms
increasetypicalsignsofmeasles(conjuctivitis,coryza,coughandfeverfollowedbyrash)appear.1,3,12

Acutecomplications
MVinfectionaffectsmultipleorgansystemsandcomplicationsaremostcommoninthefirst46wk
afteranacutephaseandupontheimmunefunctionsaredisturbed.Althoughsymptomsarerelatively
common,theseverityrangesfrommildandlessserioussuchasdiarrheatomoreserioussuchas
pneumonia(eitherviralpneumoniaorsecondarybacterialpneumonia),laryngotracheobronchitis,otitis
media,cornealulceration(leadingtocornealscarring),stomatitisandencephalitis.Complicationsare
usuallymoresevereinadultswhocatchthevirus,inmalnourishedandimmunecompromised
individuals.

Complicationswithpregnancy
Measlesremainsarareeventinpregnancyindevelopingcountriessincemostwomenofchildbearing
ageacquiredmeaslesatayoungage.13However,inindustrializedcountriestheagedistributionof
measlescasesischangedbyimmunization,resultinginmeaslesinfectioninyoungadults.Thus,
infectionofMVseronegativewomenwouldparticularlycauseseriouscomplicationsincluding
pneumonitis,hepatitis,prematurelabor,fetallossandanincreasedriskofmaternaldeath.

Delayedcomplications
Laterordelayedcomplicationsincludeaprolonged/increasedsusceptibilitytootherinfectionsthat
occurmainlywithimmunecompromisedindividuals.14,15

Subacutesclerosingpanencephalitis(SSPE)isanotherlatecomplicationofMVthatleadstodeath.The
mechanismofinfectionanditsdevelopmentremainsambiguous.However,MVisimplicatedinthe
developmentoftheneurologicaldiseasesSSPE.16,17SSPEcanbepresentmanyyearsaftertheacute
disease.Itischaracterizedbyaninsidiousonsetofaprogressivecerebraldysfunctionoccurringovera
courseofmonths,andsometimesmoreduetoslowprogressivedeteriorationofpartsofthenervous
system.Theinitialsymptomscaninvolvethealterationinpersonalityanddeterioratingperformance
withperiodsofremissions.Theclinicaldiagnosisisconfirmedbythedetectionofserummeasles
antibodiesintheCSF.Theneuropathologyisaccompaniedbyneuraldemyelination,andlesions
involvethecerebralcortex,hippocampus,cerebellarcortex,basalganglia,brainstemandspinal
cord.1618AlthoughMVantigensweredetectablewithintheneuronsandglialcells,theviruswas
defectiveinavarietyofwaysandcouldnotbeculturedorisolateddirectlyfromthebraintissuesithas
beenrescuedbyfusingtheexplantswithindicatorcellsthatallowedtransmissionofinfection.19The
recoveredMVcontainedhypermutationswithintheORFsofM,F,andH(seebelow).Onlylately,the
modeofMVtransmissioninneuronswasshownretrogradetosynapsisinHippocampalslice
cultures.20

Fatalityrates
Thedeathrateinthe1920swasaround30%ofallinfectedindividualswhereasnow,withimproved
hospitalizationandhealthcaresystems,becamelessthan0.5%indevelopedcountries.Inpopulations
withhighlevelsofmalnutritionandalackofadequatehealthcare,mortalityremainsashighas10%.In
casesofseriouscomplications,theratemayriseto2030%.21Increasedimmunizationhasledtoa60
75%dropinmeaslesdeathswhichmadeup25%ofthedeclineinmortalityinchildrenunderfive.22

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Althoughthemortalityrateasaconsequenceofmeaslesisdeclining,manyriskfactorsremain
unsolved:

RiskfactorsforMVinfection
(1)ChildrenwithimmunodeficiencyduetoHIVorAIDS,leukemia,ormalnourishedregardlessof
immunizationstatus.14,15,23(2)Traveltoareaswheremeaslesisendemicorcontactwithtravelersto
endemicareas.(3)Infantswholosepassiveantibodybeforetheageofroutineimmunization.3,24

MeaslesVaccine Goto:

MVvaccineswerepreparedfromlivewildtypestrainsthathavebeenculturedunderconditionsthat
causedthemtolosevirulencewithoutlosingtheirabilitytoinduceimmunity.MVwasisolatedin
tissueculturefromthebloodsamplesandthroatswabstakenfromastudent(DEdmonston)suffering
fromMVinfection.25Theabilitytopassagethevirusintissuecultureledtothedevelopmentofthe
firstmeaslesvaccinein1963.26,27Bothliveandkilledvaccineswereinitiallydeveloped.The
inactivatedvaccineprovidedonlyshorttermprotectionandinducedpoorTcellresponsesand
antibodythatdidnotundergoaffinitymaturation.28Theresponsetothisvaccinecausedanatypical
measles,amoresevereformofmeasles,29andwaswithdrawn.30Theliveattenuatedvaccine
Edmonstonstrainwashighlyreactogenic,thusgammagloblulinwasoftenadministered
simultaneouslywiththisvaccine.28Bythemid60snewstrainsofMVvaccinesweredevelopedby
furtherpassagingoftheEdmonstonvaccinesincellcultures(chickenembryos,chickenembryo
fibroblasts,sheepkidney,dogkidneyandhumandiploidcells).Thismethodallowedthegenerationof
thefollowingcommercialvaccines:theEdmonstonZagreb,Schwarz,AIKC,Moraten,Attenuvax,and
Rubeovax.Separateisolates,Leningrad16andCAM70,werealsopassagedinthesamemannerto
generateasaferMVvaccine.31,32Theseattenuatedvaccineswerelessreactogenicandweremore
suitableforuseinvaccinationcampaignswithoutconcomitantadministrationofgammaglobulin.33

Vaccinationcoverage

Indevelopedcountries,childrenareimmunizedagainstmeaslesbytheageof18mo,generallyaspart
oftheMMRvaccine(measles,mumps,andrubella).Thevaccinationisgenerallygivenatthisageto
avoidtheinteractionofthevaccinewithmaternalantiMVantibodiesthatmaypreventthevaccine
virusesfrombeingeffective.3Aseconddoseisusuallygiventochildrenbetweentheagesoffourand
five,toincreaseratesofimmunity.Vaccinationrateshavebeenhighenoughtomakemeaslesrelatively
uncommondisease.Themostcommonadversereactionstovaccinationarefeverandpainatthe
injectionsite.Lifethreateningadversereactionsoccurinlessthanonepermillionvaccinations
(<0.0001%).34

Indevelopingcountries,wheremeaslesishighlyendemic,WHOrecommendstwodosesofvaccinebe
givenatsixandninemonthsofage.ThevaccineshouldbegivenwhetherthechildisHIVinfectedor
not.35,36ThevaccineislesseffectiveinHIVinfectedinfantsthaninthegeneralpopulation,butearly
treatmentwithantiretroviraldrugscanincreaseitseffectiveness.

UndertheGlobalVaccineActionPlan,measlesandrubellaaretargetedforeliminationbyWHOby
2020,however,thepersistenceofthediseasecouldbeastumblingblocktoglobaleradication.Ithas
provendifficulttovaccinateasufficientnumberofchildreninEuropeandworldwidetoeradicatethe
disease,becauseofoppositiononphilosophicalorreligiousgrounds,orfearsofsideeffects,orbecause
someminoritygroupsarehardtoreach,orsimplybecauseparentsforgettohavetheirchildren
vaccinated.Inaddition,vaccinationisnotmandatoryinsomecountriesinEurope,incontrasttothe
UnitedStatesandmanyLatinAmericancountries,wherechildrenmustbevaccinatedbeforetheyenter
school.37

Impactofvaccination
VaccinationagainstMVhashadamajorimpactontheepidemiologyofmeasles.Beforethevaccine
becameavailabletheoreticallyallchildrencontractedmeasles.38Anestimated130millioncasesand
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around7milliondeathsoccurredgloballyeachyear.3TheconcertedactivitiesofGovernments,
agenciesandtheExpandedProgramonImmunization(EPI)haveresultedindramaticincreasein
coverageofvaccination.Worldwide,thefatalityratehasbeensignificantlyreducedbyavaccination
campaignledbypartnersintheMeaslesInitiative:theAmericanRedCross,theUnitedStatesCenters
forDiseaseControlandPrevention(CDC),theUnitedNationsFoundation,UNICEFandtheWHO.
Globally,measlesfellsignificantlyfromanestimated873,000deathsin1999to345000in2005andto
56000in2014(Table1).39

Table1.ReportedmeaslescasesaccordingtoWHOstatistics

Administrationofmeaslesvaccines
Measlesvaccinesareusuallyadministeredsubcutaneousofthefreezedriedvaccinereconstitutedin
salinesolutionorsterile/distilledwater.Thereconstitutedvaccineisadministeredin0.5mLdose
containingnotlessthan1000TCID50(tissuecultureinfectiousdoses)oflivemeaslesvirus.
Administrationofthevaccinebyanalternativeroute(Aerosol)wasalsopracticedandhasgiven
equivalentseroconversionratestothesubcutaneousrouteinmoststudies.40Separatestudiesusing
nebulizersonschoolchildrenhaveshownsuperiorityofaerosolapplicationtosubcutaneousroute,
especiallyinpreimmunechildren.4143

Immunogenicityofmeaslesvaccine
Thevaccineishighlyimmunogenicwhenitisgiveninthecorrectdosetochildrenofappropriateage.
Thefactthatmeaslesvaccinesareliveattenuated,theyhavetheabilitytoinfectandreplicateinthe
hostwithoutcausingsymptomsofthewildtypestrain.ThisallowsMVvaccinetoefficientlyinteract
withvariousarmsoftheimmunesystemandinducelonglivedimmunityagainstthecognatewildtype
strain.Severalstudiesreportedthatimmunizationcaninduceprotectionupto20y,44,45andthateven
withthefalloftheantibodylevels,reexposuretothewildtypestrainstimulatesasecondaryresponse
inwhichIgGlevelsriserapidlyandpeakapproximately1012dpostexposure.46Inthemajorityof
vaccinatedpersonsreinfectionwiththewildtypewillonlycausesubclinicalboostofantibodylevels.
Casesofclinicalmeasleshavebeendocumentedinpersonswhohadsecondaryvaccinefailure.47

DevelopmentoftechniquesthatallowtherescueofMVfromcDNA Goto:

Thetwentiethcenturysawtheintroductionofseveralsuccessfulvaccines,includingthoseagainst
Diphtheria,Measles,Mumps,Rubella,Influenza,HepatitisB,andyellowfeverthatsavedmillionsof
livesworldwideinadditiontotheeradicationofsmallpox.DuetotheexcellentsafetyrecordofMV
livevaccinestheywereemployedinmanylabstounderstandthemolecularmechanismsof
paramyxovirusinfection.However,theresearchinthisfieldwaslaggingduetothelackofessential
toolstounderstand,attenuation,intracellulartransportandassemblyaswellaspathogenesis.The
developmentofreversegeneticstechnologiestoallowtherescueofnonsegmentednegativestrand
RNAvirusesfromcDNA48enabled:(1)insightsonthegenomicmodificationofavarietyofMV
isolatesandthebiologyoftheseviruses(2)insertionofmarkergenesequencestoallowlocalizationof
virusreplicationandinfection(3)developmultivalentrecombinantvaccinesagainstmeaslesandother
pathogensand,(4)engineercandidateoncolyticvirusesagainstcancer.

InsightsonthegenomicmodificationofMVanditsbiology
OneofthedrivingforcesbehindthereversegeneticsofMononegaviraleswastogainbetterinsight
intothebiologyofthisviralorder.Infactsitespecificmutations,ORFeliminationormodification
withintheMVgenomebecamepossibletoanswerthelaggingquestions.Theroleofthelong
untranslatedregion(UTR)oftheFusion(F)orMatrix(M)genesonvirusreplicationandpathogenesis
werestudiedbygeneticmanipulationofthefulllengthMVgenome.Alargedeletionof504
nucleotidesofthe5UTRoftheFgenedidnotshowanypropagationdeficitincellculture.However,
inhumanthymus/liverimplantsengraftedtoSCIDmice,thismutantreplicatedslowerandthetiters
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49 4/12
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49
were10foldlowerthantheparentalstrain. otherstudies,usingthesametechnology,foundthatthe
3UTRoftheMgeneaswellasthe5UTRoftheFgene,haveacrossregulatoryfunctiononthe
magnitudeofFandMexpression,thusinhibiting/compromisingMVreplicationandreducingits
pathogenesis.50GeneticallyengineeredwtMVmutantsdevoidofthesmallproteinsVandC(MVV
andMVC)replicatedlessextensivelyinmacaquesbecausetheywererestrictedbyinterferonand
inflammatoryresponses.51Finally,thefunctionoftheMproteinwasaddressedbyeithereliminationof
theORForbyreplacementofthisORFbythatofSSPEmutant.ItwasfoundthatMproteinregulates
virusenvelopeproteinssortingandbuddinginpolarizedepithelialcells52andtheothermutant
replicatedefficientlyinprimarybraincellsaswellasthebrainsoftransgenicmicesusceptibletoMV
infection.53

Insertionofmarkergenesequencestoallowviruslocalization
Insertionofreadingframesencodingvariousmarkerproteinsisusefulformonitoringthepathwayof
MVspreadandreplicationincellsandintheorgansofinfectedanimals.Thegreenfluorescentprotein
(GFP)wasextensivelyusedasamarkergenetostudyprogressofinfection5456andtransmissionof
thevirusthroughsynapsisinhippocampalslicecultures.20,57TheGFPexpressedbyMVprovedtobe
mostinformativeinstudiesonthebiodistributionofMVinfectedcellsintransgenicmice.58

Developmentofmultivalentrecombinantandchimericvaccinecandidates
ThemodificationofMVgenomebyenrichmentofitsgenomebyadditionalgenesandthemodification
ofitstropismwasestablisheduponproofofconcepttodetermine:(1)thecapacityofMVgenometo
accommodatelargeinserts(exceeding6kb)ofmarkergenesexpressedsimultaneouslybythesame
virus(GFP,LacZ,CAT)55and(2)tostablyexpresslargegeneinsertsofotherpathogens,andthatthe
recombinantMVinducesquantitativeimmuneresponseagainstitselfandtheclonedgeneproducts.59
62
IntensiveresearchwasspentonthisfronttogenerateavarietyofrMVsemployingclinically
approvedMVvaccinestrains.32,60,63RecombinantMVsexpressingsingleormultiplegenesof
HIV61,62,64,65intwodistantMVvaccinebackbonesanddifferentHIVgeneinserts,induced
significantimmuneresponses(humoralandcellular)againstthevector(MV)andtheinsertedantigens
(HIVenvandgag)uponimmunizationoftransgenicmice.ManyotherimportantrMVswere
developedintheselabs(InstitutePasteurandUniversityofZurich/BernaBiotech),inducing
neutralizingantibodies(IgG)andcellularimmuneresponses(CD8+Tcells)againstSARSCoV,66
HPV,67WNV68andDenguefever69inadditiontomanyotherexperimentalMVrecombinants.64

PreexistingimmunitytowardMV(morethan90%ofthepopulationiseithervaccinatedornaturally
immunized)hasbeenacontinuousconcern,especiallysincerMVswouldtargetnotonlytheinfantsbut
alsoadults.Arecentstudyaddressingthisconcernshowedthatthepreexistingantibodytitersabove
500mIUpermlofserumisinhibitorytorMVimmunizationandthusahigherdosetoprimean
immuneresponsemaybenecessary.70Inaddition,analternativeroutetoapplicationofrMVto
circumventpreexistingantibodieswouldbetheaerosolroute.4143,70

EngineeringofcandidateoncolyticMVsagainstcancer
Tospecificallyinfectanddestroycancercellswasillusiveforlongtime,however,methodstoengineer
viruses,withintrinsiccytolyticfunction,tospecificallytargetcancercellsisnowatreach.A
revolutionaryapproachwasdoneaftertherescueofMVfromcDNA.48Thistechnologyallowed
geneticengineeringoftheMVgenomeatwilltogenerateamutantthatisfullyreplicating.A
primordialsteptowardengineeringatargetedMVwastodeterminewhetherenvelopeswapsor
modificationoftheattachmentproteinsHand/orisfeasible.Theswapoftheviralenvelope
glycoproteins(FandH)byanenvelopeglycoproteinofadifferentvirus(VSVG)waspractically
efficientandthenovelchimericvirus(MVVSV)replicatedinavarietyofcellsincludingcellslines
thatarenotsusceptibletoMV,indicatingachangeinthetropismofMV.Inaddition,thechimericvirus
inducedprotectiveimmunitytoVSVsusceptiblemice.Aheterologouschallengeoftheseanimalswith
10foldlethaldoseofVSVwasnoteffective.71,72Thesefindingopenedthewaytowardgenetic

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manipulationofMVenvelopeproteinstospecificallytargetCancercells.Indeed,researchersatMayo
ClinicwereabletogeneratevariousmutantMVsthattargetspecificcells.73However,beforeprobing
anengineeredMVinclinicaltrialsitwasnecessarytodeterminewhetherstandardMVvaccineitselfis
safeandefficaciousforuseinpatientswithcancerandwhetherMViscytolytictocancercells,as
observedinexperimentalanimalmodel.74AdecisiveclinicaltrialperformedattheUniversityHospital
ZrichSwitzerlandthatprovidedtheproofofconceptonusingMVasanoncolyticvector.7476
ImportantdevelopmentinthisfieldwascrownedwithclinicaltrialsledbyMayoClinicUSAusing
geneticallymodifiedMVandshowedpositiveimpactandapromisingprospectivefortheuseofMV
vectoragainstcancer.7880

DisclosureofPotentialConflictsofInterest Goto:

Nopotentialconflictsofinterestweredisclosed.

Acknowledgment Goto:

Thisreviewisdedicatedtothememoryofmyfatherwhowasasourceofinspiration.Inremembrance
ofmycolleagueandfriendSteveUdem,forhisdocumentedinputinthefieldofMononegavirales
reversegenetics.IwouldliketothankallmembersofmyGroupwhocontributedtothesuccessofMV
vector.TheworkontheHIVresearchatmyLabwassupportedbyNIHgrantAI46007andcontract
No.HHAS266200600018CtoH.Y.N.

Glossary Goto:

Abbreviations:

MV measlesvirus

rMV recombinantmeaslesvirus,SSPE,subacutesclerosingpanencephalitis

CSF cerebrospinalfluid

SLAM signalinglymphocyteactivationmolecule

HIV humanimmunodeficiencyvirus

HPV humanpapillomavirus

WNV westnilevirus

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